Novel controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum

ABSTRACT

The present invention provides a controlled release device for sustained or pulsatile delivery of pharmaceutically active substances for a predetermined period of time. This invention further provides such device in which sustained or pulsatile delivery is obtained by the unique blend and Inmate mixture of pharmaceutically active substances with a microbial polysaccharide and uncrosslinked linear polymer and optionally a crosslinked polymer and/or lipophillic polymer and/or saturated polyglycolyzed glyceride. The invention also provides a process for the manufacture of such devices and pharmaceutical compositions containing the same.

FIELD OF THE INVENTION

[0001] The present invention relates to a controlled release devicewhich provides sustained or pulsatile delivery of pharmaceuticallyactive substances for a predetermined period of time. This inventionfurther relates to such device in which sustained or pulsatile deliveryis obtained by the unique blend and intimate mixture of pharmaceuticallyactive substances with a microbial polysaccharide and uncrosslinkedlinear polymer and optionally a crosslinked polymer and/or lipophillicpolymer and/or saturated polyglycolyzed glyceride. The invention alsorelates to a process for the manufacture of such devices andpharmaceutical compositions containing the same.

BACKGROUND OF THE INVENTION

[0002] The prior art teaches many systems for the delivery ofpharmaceutically beneficial agents. One such system operates by means ofan osmotic pumping mechanism. However, it suffers from being verycomplex and is complicated to manufacture. A second type ofpharmaceutical delivery system utilizes hydrogels either from a groupconsisting of uncrosslinked linear polymers or from a group consistingof crosslinked polymers. In devices using uncrosslinked polymers,viscosity is the rate controlling factor for drug release kinetics. Inthese systems a gelatinous layer is formed on the surface uponhydration. The thickness and durability of this gelatinous layer dependsupon the concentration, as well as the molecular weight and viscosity ofthe polymer in the device. At higher concentrations the linear polymerchains entangle to a greater degree leading to virtual crosslinking anda stronger gel layer. Drug release is by the dissolution of polymer anderosion of the gel layer and hence the rate of erosion is what controlsthe release rate.

[0003] Although viscosity is an important consideration in controlleddrug release from hydrogel matrices, it is viscosity under low shearconditions that control diffusion through the matrix.

[0004] Several U.S. Patents are directed to the various pharmaceuticaldelivery systems as mentioned above, see for example U.S. Pat. Nos.3,845,770, 3,916,899, 4,016,880, 4,160,452 and 4,200,098. While thesesystems do provide for the delivery of a selected pharmaceutical agent,none of these provide a controlled or pulsatile delivery of thepharmaceutical agent in which drug release is modulated by combining amicrobial polysaccharide and uncrosslinked polymer. Furthermore, none ofthe prior art teaches a device comprising a microbial polysaccharide anduncrosslinked polymer and optionally a crosslinked polymer and/orlipophillic polymer and/or saturated polyglycolyzed glyceride.

[0005] Theme was therefore a need to develop a novel controlled releasepharmaceutical delivery device which could be made in a cost efficientmanner and provide for either sustained or pulsatile delivery of theselected pharmaceutical incorporated therein.

SUMMARY OF THE INVENTION

[0006] It is an object of the present invention to provide a novelcontrolled pharmaceutical release device capable of delivering in acontrolled, continuous or pulsatile manner therapeutically effectiveamounts of pharmaceutically active agent for a predetermined period oftime in mammals, especially human beings.

[0007] According to an object of the present invention is a controlledpharmaceutical release device for use with a selected pharmaceutical toprovide continuous or pulsatile therapeutically effective amounts of thepharmaceutical, the device comprising;

[0008] about 1 to 60% by weight microbial polysaccharide; and

[0009] about 1 to 60% by weight uncrosslinked linear polymer.

[0010] The device may optionally comprise about 1 to 50% by weightcrosslinked polymer, about 1 to 50% by weight lipophillic polymer and/or1 to 50% by weight saturated polyglycolyzed glyceride.

[0011] According to another object of the present invention is apharmaceutical composition which provides controlled release of thepharmaceutical contained therein, said composition comprising;

[0012] about 1 to 60% by weight microbial polysaccharide;

[0013] about 1 to 60% by weight uncrosslinked linear polymer; and

[0014] about 1 to 80% by weight pharmaceutical active

[0015] The composition may optionally comprise about 1 to 50% by weightcrosslinked polymer, about 1 to 50% by weight lipophillic polymer and/or1 to 50% by weight saturated polyglycolyzed glyceride.

[0016] According to yet a further object of the present invention is amethod for making a controlled release formulation of pharmaceuticallyactive agents, said method comprising,

[0017] blending about 1 to 80% by weight pharmaceutical active withabout 1 to 60% by weight microbial polysaccharide and about 1 to 60% byweight uncrosslinked linear polymer to form a homogeneous blend;

[0018] granulating said homogeneous blend and kneading to form wetgranules;

[0019] drying the wet granules to a loss on drying of about <<5%;

[0020] size reducing the dried granules to provide a granule size ofabout <1400 microns;

[0021] blending the dried granules with about 0.5 to 10% lubricant; and

[0022] compressing the lubricated granules into tablets.

[0023] Preferably, the pharmaceutically active agent is intimately mixedwith a microbial polysaccharide and uncrosslinked linear polymer andfurther wet granulated, dried, sieved, lubricated and pressed intotablets.

[0024] Optionally, to the mixture of pharmaceutical active, microbialpolysaccharide and uncrosslinked linear polymer may be added about 1 to50% by weight crosslinked polymer, about 1 to 50% by weight lipophillicpolymer and/or 1 to 50% by weight saturated polyglycolyzed glyceride afiber aspect of this invention there is provided a method for deliveringsoluble or poorly soluble pharmaceutically active agents by deliberateand expert manipulation of the composition and ratios of a microbialpolysaccharide, preferably xanthan gum, and uncrosslinked linearpolymer, preferably hydroxypropylmethyl cellulose polymers, present inthe device. The composition and ratios of the optional crosslinkedpolymer, preferably Carbopol 971P, and/or lipophillic polymer,preferably glyceryl behenate, and/or saturated polyglycolyzed glyceride,preferably gelucire 44/14, may also be manipulated to vary the type ofrelease provided.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The novel controlled delivery device of the present inventionprovides the controlled release of a selected pharmaceutically activeagent in a sustained or a pulsatile manner. In one embodiment, thedevice is formulated as a composition comprising pharmaceutically activeagents in a sustained release matrix tablet. In another embodiment, amethod is provided for making the controlled release pharmaceuticaldelivery device.

[0026] The present invention is simple in fabrication, permittingefficient and reproducible mass production by conventional techniques.

[0027] The device comprises a mixture of about 1 to 60% by weightuncrosslinked linear polymers and about 1 to 60% by weight microbialpolysaccharides to which about 1 to 80% by weight selectedpharmaceutical active is added. Suitable pharmaceuticals for use in thedevice include but are not restricted to diltiazem, glipiztide,buspirone, tramadol, gabapentin, verapamil, etodolac, naproxen,diclofenac, COX2 inhibitors, budesonide, venlafaxme, metoprolol,carbidopa, levodopa, carbamazepine, ibuprofen, morphine,pseudoephedrine, paracetamol, cisapride, pilocarpine, methylphenidine,nifedipine, nicardipine, felodipine, captopril, terfenadine,pentoxifylline, fenofibrate, aciclovir, zidovudine, moclobemide,potasium chloride, lamotrigine, citalopram, cladribine, loratadine,pancrelipase, lithium carbonate, orphenadrine, ketoprofen, procainamide,ferrous sulfate risperidone, clonazepam, nefazodone, lovastatin,simvastatin, pravachol, ketorolao, hydromorphone, ticlopidine,seligiline, alprazolam, divalproex and phenytoin.

[0028] Uncrosslinked linear polymers suitable for use in the presentinvention are cellulose ethers preferably hydroxypropylmethyl cellulose(HPMC). Suitable microbial polysaccharides for use in the inventioninclude xanthan gum.

[0029] The device may optionally comprise about 1 to 50% by weightcrosslinked polymer, preferably Carbopol 971 P. about 1 to 50% by weightlipophillic polymer, preferably glyceryl behenate, glycerylpalmitostearate or glyceryl, and/or 1 to 50% by weight saturatedpolyglycolyzed glyceride, preferably gelucire 44/14.

[0030] The device may optionally include about 0.5 to 10% by weightlubricants such as for example magnesium stearate and/or talc as well asabout 0.5 to 10% by weight granulating or tabletting aids such assilicone dioxide, microacrystallino cellulose. calcium phosphate, sodiumlaurel sulphate, calcium sulphate and silicified microcrystallinecellulose.

[0031] The device can be fabricated with any suitable pharmaceuticalactive as a tablet, a film coated tablet or a capsule for easyingestion.

[0032] It was unexpectedly found that controlled delivery devicescomprising xanthan gum and uncrosslinked linear polymers together in anintimate mixture with a pharmaceutically active agent perform efficientand optimal controlled release of the pharmaceutical active than ifeither polymer were to be used alone. It was also found that suchdelivery devices when additionally comprising crosslinked polymersand/or lipophillic polymers and/or saturated polyglycolyzed glyceridealso provides efficient controlled release of the pharmaceutical activecontained therein. Uncrosslinked linear polymers such ashydroxypropylmethyl cellulose (MC) tend to become more newtonian at lowshear and the viscosity becomes independent of shear rate. Xanthan gumon the other hand displays a pseudoplastic nature in which there is alinear dependence of viscosity as a function of the shear rate. At lowshear rates xanthan gum has higher viscosity compared tohydroxypropylmethyl cellulose (these differences are larger at evenlower shear rates) while the opposite is the case at higher shear rates.During transit in the gastrointestinal tract (GIT) a matrix controlleddelivery device encounters regions of turbulence and non turbulence. Itis hypothesized that regions of non turbulence present lower shear ratesto the matrix tablets, conditions for which xanthan gum demonstrateshigher viscosity than HPMC while regions of turbulence present highershear rates to the matrix tablet, conditions for which HPMC demonstratea higher viscosity than xanthan gum. Since matrix devices rely on thedevelopment of a viscous layer around the tablet to control diffusion ofthe drug from the surface and interior of the tablet, the use of xanthangum alone in a matrix tablet will presumably be more efficient inregions of non turbulence while HPMC matrices will be more efficient inregions of turbulence. However, since these tablets encounter bothenvironmental conditions, a controlled delivery device comprising ofboth xanthan gum and HPMC together in intimate mixture with thepharmaceutically active agent(s) will provide optimum controlledperformance.

[0033] According to one embodiment of the present invention is thepreferred form of the sustained release device which is presented as amatrix tablet that is prepared using the following steps:

[0034] Step 1. Intimately blending a pharmaceutically active agent(s)(about 1-80% by weight) with about 160% by weight of xanthan gum andabout 1-60% by weight of hydroxypropylmethyl cellulose (preferablyMethocel™ premium grade type K100M CPR or K4M CR) in a planetary or highshear mixer.

[0035] Step 2. Granulating the homogeneous blend from step 1 with agranulating solution (preferably isopropyl alcohol) in a planetary orhigh shear mixer. It is preferable to knead the wet mass for about 1-3minutes after wet granulation.

[0036] Step 3. Drying the wet granules in a fluid bed dryer or traydryer to a loss on drying (LOD) of about <5%. Preferably they are driedin a tray dryer at about >40° C. to an LOD of about <%;

[0037] Step 4. Size reduction of the dried granules from step 3 is donein a mill, preferably a Cone mill, such that granule size is about <1400microns.

[0038] Step 5. Intimately blending the milled granules with about0.5-10% by weight of magnesium stearate and/or about 0.5 to 10% byweight talc in a V-blender.

[0039] Step 6. The lubricated granules from step 5 are compressed intotablets using a rotary tablet press. The resulting tablets have ahardness of about >5 Strong Cobb units and a friability of about <1%.

[0040] Step 7. Optional Other granulating or tabletting aids such assilicone dioxide, microcrystalline cellulose and calcium phosphate canbe added into step 5.

[0041] Step 8. Optional The tablet produced in step 6 can be film coatedwith a suitable coating. Such coatings are well known in the art ofpharmaceuticals. One skilled in the art would readily comprehend thetype of film coating materials and quantity that may be used in thepresent invention

[0042] Depending upon the conditions under which the materials areprocessed and the depending on the relative proportions of the severalcomponents, one obtains a product of unique sustained releasecharacteristics. The sustained release characteristic of the compositioncan be predetermined and varied by adjusting the makeup of thecomposition within the aforesaid limits. The duration, uniformity andcontinuity of release of the pharmaceutically active agent(s) can besuitably controlled by varying the relative amount of the xanthan gumand HPMC.

[0043] Pulsatile delivery is achieved by making a unit dose such as acapsule containing a plurality of tablets or population of granuleswhich release the active agent at different rates or at different timeintervals so that, for example, if one tablet or population of granulesstarts releasing first and reaches a peak, another can start and peak asthe previous one is declining. This results in pulsatile delivery.

[0044] For a sustained release effect one population or a uniform matrixis used which releases the pharmaceutical active gradually. A desiredrate is obtained by manipulating quantities in the composition.

[0045] When the delivery device of this invention is administered to thegastrointestinal tract by oral route it comes into contact with anaqueous environment and hydrates forming a gelatinous layer. Duringtransit in the gastrointestinal tract it encounters regions of nonturbulence and turbulence which presents lower shear rates and highershear rates respectively. Matrix devices rely on the development of aviscous layer around the tablet to control diffusion of the drug fromthe surface and interior of the tablet. On a comparative basis xanthangum gives higher viscosity at lower shear rates and HPMC give higherviscosity at higher shear rates. Therefore, the use of either xanthangum or HPMC alone in a matrix tablet will not give an optimumperformance when compared to matrix tablets comprising of both xanthangum and HPMC together in intimate mixture with the pharmaceuticallyactive agent(s). The present invention consist of a controlled deliverydevice capable of optimum performance in the GIT in which the activeagent is in intimate mixture with both xanthan gum and HPMC andoptionally crosslinked polymer and/or lipophillic polymer and/orsaturated polyglycolyzed glyceride in a matrix.

EXAMPLES

[0046] The examples are described for the purposes of illustration andare not intended to limit the scope of the invention.

[0047] Methods of synthetic chemistry, pharmacy and pharmacologyreferred to but not explicitly described in this disclosure and examplesare reported in the scientific literature and are well known to thoseskilled in the art. EXAMPLE 1 Diltiazem hydrochloride ER tablets %composition Diltiazem hydrochloride 30 Xanthan gum 30Hydroxypropylmethyl cellulose K100M CR 38 Talc  1 Magnesium stearate  1

[0048] Diltiazem hydrochloride was blended with xanthan gum andhydroxypropylmethyl cellulose in a high shear mixer until a homogeneousmixture was obtained. The mixture was granulated with isopropyl alcoholand dried in fluid bed dryer to a loss on drying of about <2.0%. Thedried granules were passed through a sieve #14 mesh. The milled granuleswere blended with talc and magnesium stearate for 5 minutes in aV-blender. Finally, the treated granules were pressed into tablets usinga rotary tablet press. EXAMPLE 2 Diltiazem hydrochloride ER tablets %composition Diltiazem hydrochloride 30 Microcrystalline cellulose 10Xanthan gum 25 Hydroxypropylmethyl cellulose K100M CR 33 Talc  1Magnesium stearate  1

[0049] Diltiazem hydrochloride was blended with microcrystallinecellulose, xanthan gum and hydroxypropylmethyl cellulose in a high shearmixer until a homogeneous mixture was obtained. The mixture wasgranulated with isopropyl alcohol and dried in fluid bed dryer to a losson drying of about <2.0%. The dried granules were passed through a sieve#14 mesh. The milled granules were blended with talc and magnesiumstearate for 5 minutes in a V-blender. Finally, the treated granuleswere pressed into tablets using a rotary tablet press. EXAMPLE 3Glipizide ER tablet % composition Glipizide 4 Microcrystalline cellulose20  Xanthan gum 40  Hydroxypropylmethyl cellulose K100M CR 33  Siliconedioxide 1 Talc 1 Magnesium stearate 1

[0050] Glipizide was blended with silicone dioxide, microcrystallinecellulose, xanthan gum and hydroxypropylmethyl cellulose in a high shearmixer until a homogeneous mixture was obtained. The mixture wasgranulated with isopropyl alcohol and dried in fluid bed dryer to a losson drying of out <2.0%. The dried Jules were passed through a sieve #14mesh. The milled granules were blended with talc and magnesium stearatefor 5 minutes in a V-blender. Finally, the treated granules were pressedinto tablets using a rotary tablet press. EXAMPLE 4 Glipizide ER tablet% composition Glipizide 4 Microcrystalline cellulose 20  Xanthan gum 40 Hydroxypropylmethyl cellulose K4M CR 33  Silicone dioxide 1 Talc 1Magnesium stearate 1

[0051] Glipizide was blended with silicone dioxide, microcrystallinecellulose, xanthan gum and hydroxypropylmethyl cellulose in a high shearmixer until a homogeneous mixture was obtained. The mixture wasgranulated with isopropyl alcohol and dried in fluid bed dryer to a losson drying of about <2.0%. The dried granules were passed through a sieve#14 mesh. The milled granules were blended with talc and magnesiumstearate for 5 mutes in a V-blender. Finally, the treated granules werepressed into tablets using a rotary tablet press. EXAMPLE 5 NaproxynSodium ER tablets % composition Naproxyn sodium 55 Microcrystallinecellulose 10 Xanthan gum 10 Hydroxypropylmethyl cellulose K100M CR 18Carbopol 971P NF  5 Talc  1 Magnesium stearate  1

[0052] Naproxyn sodium was blended with microcrystalline cellulose,xanthan gum and hydroxypropylmethyl cellulose in a high shear mixeruntil a homogeneous mixture was obtained. This mixture was granulatedwith isopropyl alcohol and dried in fluid bed dryer to a loss on dryingof about <2.0%. The dried granules were then passed through a sieve #14mesh. The dried granules were blended with Carbopol 971P for 10 minutes,then with talc and magnesium stearate for 5 minutes in a V-blender.Finally, the treated granules were pressed into tablets using a rotarytablet press. EXAMPLE 6 Naproxyn Sodium ER tablets % compositionNaproxyn sodium 55 Microcrystalline cellulose 10 Xanthan gum 10Hydroxypropylmethyl cellulose K100M CR 14 Gelucire 44/14  9 Talc  1Magnesium stearate  1

[0053] Naproxyn sodium was blended with microcrystalline cellulose,xanthan gum and hydroxypropylmethyl cellulose in a high shear mixeruntil a homogeneous mixture was obtained. This mixture was granulatedwith Gelucire isopropyl alcohol solution and dried in a fluid bed dryerto a loss on drying of about <2.0%. The dried granules were then passedthrough a sieve #14 mesh. The milled granules were blended with Carbopol971P for 10 minutes, then with talc and magnesium stearate for 5 minutesin a V-blender. Finally, the treated granules were pressed into tabletsusing a rotary tablet press. EXAMPLE 7 Verapamil Hydrochloridc ERtablets % composition Verapamil Hydrochloride 50 Microcrystallinecellulose 14 Xanthan gum 10 Hydroxypropylmethyl cellulose K100M CR 14Compritol 888 ATO 10 Talc  1 Magnesium stearate  1

[0054] Verapamil hydrochloride was blended with microcrystallinecellulose, xanthan gum, hydroxypropylmethyl cellulose and Compritol in ahigh hear mixer until a homogeneous mixture was obtained. This wasgranulated with isopropyl alcohol and dry in fluid bed dryer to a losson drying of about <2.0%. The dried granules were then passed through asieve #14 mesh. The milled granules were blended with Carbopol 971P for10 minutes, then with talc and magnesium stearate for 5 minutes in aV-blender. Finally, the treated granules were pressed into tablets usinga rotary tablet press. EXAMPLE 8 Citalopram hydrobromide % compositionCitalopram hydrobromide  5 Lactose anhydrous 30 Microcrystallinecellulose 14 Xanthan gum 10 Hydroxypropylmethyl cellulose K100M CR 14Carbopol 971P  5 Gelucire 44/14 10 Compritol 888 ATO 10 Talc  1Magnesium stearate  1

[0055] Citalopram hydrobromide was blended with microcrystallinecellulose, xanthan gum, hydroxypropylmethyl cellulose and Compritol in ahigh shear mixer until a homogeneous mixture was obtained. This mixturewas granulated with Gelucire isopropyl alcohol solution and dry in fluidbed dryer to a loss on drying of about <2.0%. The dried granules werethen passed through a sieve #14 mesh. The milled granules were blendedwith Carbopol 971P for 10 minutes, then with talc and magnesium stearatefor 5 minutes in a V-blender. Finally, the treated granules were pressedinto tablets using a rotary tablet press.

[0056] Although preferred embodiments have been described herein indetail it is understood by those skilled in the art that variations maybe made thereto without departing from the scope of the invention or thespirit of the appended claims.

What we claim:
 1. A controlled release pharmaceutical device whichprovides sustained or pulsatile delivery of pharmaceutically activesubstances for a predetermined period of time the device comprising;about 1 to 60% by weight microbial polysaccharide; and about 1 to 60% byweight uncrosslinked linear polymer.
 2. The device of claim 1, whereinsaid device additionally comprises about 1 to 80% by weightpharmaceutical active.
 3. The device of claim 2, wherein saidpharmaceutical active is selected from the group consisting ofdiltiazem, glipizide, buspirone, tramadol, gabapentin, verapamiletodolac, naproxen, diclofenac, COX2 inhibitors, budesonide,venlafaxine, metoprolol, carbidopa, levodopa, carbamazepine, ibuprofen,morphine, pseudoephedrine, paracetamol, cisapride, pilocarpine,methylphenidine, nifedipine, nicardipine, felodipine, captopril,terfenadine, pentoxifylline, fenofibrate, aciclovir, zidovudine,moclobemide, potasium chloride, lamotrigine, citalopram, cladribine,loratadine, pancrelipase, lithium carbonate, orphenadrine, ketoprofen,procainamide, ferrous sulfate risperidone, clonazepam, nefazodone,lovastatin, simvastatin, pravachol, ketorolac, hydromorphone,ticlopidine, seligiline; alprazolam, divalproex and phenytoin.
 4. Thedevice of claim 3, wherein said device additionally comprises at leastof the agents selected from the group consisting of about 1 to 50% byweight crosslinked polymer, about 1 to 50% by weight lipophillicpolymer; about 1 to 50% saturated polyglycolyzed glyceride and mixturesthereof.
 5. The device of claim 4, wherein said device additionallycomprises; about 0.5 to 10% by weight lubricant.
 6. The device of claim5, wherein said lubricant comprises magnesium stearate or talc.
 7. Thedevice of claim 1 wherein said microbial polysaccharide is xanthum gum.8. The device of claim 1, wherein said uncrosslinked linear polymer is acellulose ether.
 9. The device of claim 8, wherein said cellulose etheris hydroxypropylmethyl cellulose.
 10. The device of claim 4, whereinsaid device additionally comprises about 1 to 65% granulating ortabletting aids.
 11. The device of claim 10, wherein said granulating ortabletting aids are selected from the group consisting of siliconedioxide, microcrystalline cellulose, calcium phosphate, calciumsulphate, sodium laurel sulphate, silicified microcrystalline cellulose.12. The device of claim 4, wherein said device is fabricated as a unitdose for pulsatile delivery of the pharmaceutical active or as a uniformmatrix tablet for a sustained release of the pharmaceutical active. 13.The device of claim 12, wherein said device is formulated as a tablethaving a hardness of about >5 Strong Cobb units and a friability ofabout <1%.
 14. A pharmaceutical composition comprising; about 1 to 60%by weight microbial polysaccharide; about 1 to 60% by weightuncrosslinked linear polymer; and about 1 to 80% by weightpharmaceutical active.
 15. The composition of claim 14, wherein saidcomposition additionally comprises at least of the agents selected formthe group consisting of about 1 to 50% by weight crosslinked polymer;about 1 to 50% by weight lipophillic polymer; about 1 to 50% saturatedpolyglycolyzed glyceride and mixtures thereof.
 16. The composition ofclaim 15, wherein said composition additionally comprises about 0.5 to10% by weight lubricant.
 17. The composition of claim 16, wherein saidcomposition additionally comprises about 1 to 65% granulating ortabletting aids.
 18. A method for making a controlled releaseformulation of pharmaceutically active agents, said method comprising:blending about 1 to 80% by weight pharmaceutical active with about 1 to60% by weight microbial polysaccharide and about 1 to 60% by weightuncrosslinked linear polymer to form a homogeneous blend; granulatingsaid homogeneous blend and kneading to form wet granules; drying the wetgranules to a loss on drying of about <5%; Size reducing the driedgranules to provide a granule size of about <1400 microns; blending thedried granules with about 0.5 to 10% lubricant; and compressing thelubricated granules into tablets.
 19. The method of claim 18, wherein atleast the agents selected from the group consisting of about 1 to 50% byweight crosslinked polymer; about 1 to 50% by weight lipophillicpolymer; about 1 to 50% saturated polyglycolyzed glyceride and mixturesthereof is added to blend with said microbial polysaccharide anduncrosslinked linear polymer.
 20. The device of claim 4, wherein saidcrosslinked polymer is Carbopol 971P.
 21. The device of claim 4, whereinsaid lipophillic polymer is selected from the group consisting ofglyceryl palmitostearate, glyceryl stearate and glyceryl behenate. 22.The device of claim 4, wherein said saturated polyglycolyzed glycerideis gelucire 44/14.